Metabolism is not a Major Contributor to the Toxicity of Piperaquine, a Long-acting Antimalarial Agent in Artemisinin-based Combination Therapy
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Published:2021-12-15
Issue:10
Volume:22
Page:824-834
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ISSN:1389-2002
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Container-title:Current Drug Metabolism
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language:en
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Short-container-title:CDM
Author:
Zhang Liyuan1,
Liu Zhaohua1,
Zhang Yunrui1,
Xie Yuewu1,
Xing Jie1
Affiliation:
1. School of Pharmaceutical Sciences, Shandong University, Jinan, China
Abstract
Background:
Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic
after cumulative doses.
Objectives:
The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity
was investigated.
Method:
The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum
biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor
of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied
in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity.
Results:
Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral
doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity
was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear
pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological
examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte
apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by
PQ or M1.
Conclusions:
PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced
by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB
inflammatory pathway and p53 apoptosis pathway.
Funder
National Natural Science Foundation of China
Publisher
Bentham Science Publishers Ltd.
Subject
Clinical Biochemistry,Pharmacology
Cited by
1 articles.
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